Nonalcoholic fatty liver disease (NAFLD) is a significant risk factor for the development of hepatic insulin resistance and type 2 diabetes and is also linked to the development of other serious liver disease states including steatohepatitis, cirrhosis, and hepatic carcinoma. NAFLD is recognized as a significant health problem in the VA population. Our previous results show that mitochondrial function is linked to the development of NAFLD. Unfortunately, the mechanism(s) that govern hepatic mitochondrial function and thus alter susceptibility for hepatic steatosis remain largely unknown. Peroxisome proliferator-activated gamma co-activator alpha (PGC-1?) co-activates nuclear transcriptional factors resulting in increased mitochondrial biogenesis. Both PGC-1? and mitochondrial function are suppressed in obesity. In contrast, we have shown that in vivo liver-specific PGC-1? overexpression (o/e) increases mitochondrial function and reduces hepatic lipid accumulation. But these results may not be solely attributable to increased mitochondrial biogenesis. Recent data shows that maintenance of high quality mitochondria is also dependent on the turnover and degradation of low functioning or damaged mitochondria in the lysosome by a process termed mitophagy (i.e. autophagy of mitochondria). To that end we found that PGC-1? overexpression also increased markers of autophagy, a link that has never before been examined. This proposal will test the primary hypothesis that PGC- 1? plays a primary role in mediating a coordinated co-activation of mitochondrial biogenesis and mitophagy that is necessary for maintaining mitochondrial function and preventing and treating NAFLD. Rodent models that possess defects in mitochondrial biogenesis or mitophagy due to specific genetic alterations will be used to test the importance of the respective pathways. We will also use molecular gain of function therapy (overexpression of PGC-1?) and exercise training to modulate pathways, in addition to performing in-vitro primary hepatocyte studies to isolate hepatic specific mechanism(s) and examine acute molecular changes that underlie whole body results.
The specific aims will: 1) Determine if impaired capacity for mitochondrial biogenesis and mitophagy increases susceptibility for hepatic steatosis and insulin resistance due to reduced mitochondrial function, and 2). Test if increased mitophagy and mitochondrial function are necessary for treatment of hepatic steatosis and insulin resistance.

Public Health Relevance

Currently, 34% of the general population and 75-100% of obese and extremely obese individuals are estimated to have non-alcoholic fatty liver disease (NAFLD). NAFLD increases risk for liver complications including steatohepatitis, cirrhosis, and hepatic carcinoma. NAFLD also conveys significant metabolic risk as it plays a primary role in the development of type 2 diabetes. Current estimates suggest that incidence of fatty liver and type 2 diabetes are higher in the VA population than the general population, therefore, both disease states place significant financial strain on the VA health system, and dramatically reduce the quality of life for our US Veterans. The outcomes of this study will improve our knowledge about the mechanisms of NAFLD development and highlight potential therapeutic targets for the treatment of NAFLD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002567-03
Application #
9211278
Study Section
Endocriniology A (ENDA)
Project Start
2014-10-01
Project End
2019-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Kansas City VA Medical Center
Department
Type
Independent Hospitals
DUNS #
844272125
City
Kansas City
State
MO
Country
United States
Zip Code
64128